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Sepsis and septic shock are major healthcare problems, affecting millions of people around the world each year, with an increasing incidence. In the last decades clinical and basic research have significantly improved the understanding of the complex pathophysiology of sepsis. This led to the new sepsis definition (“Sepsis-3”) which abandoned the view that sepsis is predominately defined the various immunological responses. Rather, sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. This view with a focus on the establishment of organ failure warrants the intensified research for therapeutic attempts to prevent and treat organ failure in sepsis. In this context, it is increasingly recognized that microvascular endothelial barrier dysfunction followed by loss of microcirculatory flow are key events leading to organ failure that should be therapeutically targeted. This review summarizes the current clinical view of the novel sepsis definition and connects it to basic research aspects of endothelial barrier regulation and loss of microcirculatory flow and thus organ protection.